Efficient Synthesis and Antibacterial Profile of Bis(2-hydroxynaphthalene- 1,4-dione)

Abstract

Background: Antibacterial resistance is a serious public health problem infecting millions in the global population. Currently, there are few antimicrobials on the market against resistant bacterial infections. Therefore, there is an urgent need for new therapeutic options against these strains. Objective: In this study, we synthesized and evaluated ten Bis(2-hydroxynaphthalene-1,4-dione) against Gram-positive strains, including a hospital Methicillin-resistant (MRSA), and Gram-negative strains. Method: The compounds were prepared by condensation of aldehydes and lawsone in the presence of different L-aminoacids as catalysts in very good yields. The compounds were submitted to antibacterial analysis through disk diffusion and Minimal Inhibitory Concentration (MIC) assays. Result: L-aminoacids have been shown to be efficient catalysts in the preparation of Bis(2- hydroxynaphthalene-1,4-dione) from 2-hydroxy-1,4-naphthoquinones and arylaldehydes in excellent yields of up to 96%. The evaluation of the antibacterial profile against Gram-positive strains (Enterococcus faecalis ATCC 29212, Staphylococcus aureus ATCC 25923, S. epidermidis ATCC 12228) also including a hospital Methicillin-resistant S. aureus (MRSA) and Gram-negative strains (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853 and Klebsiella pneumoniae ATCC 4352), revealed that seven compounds showed antibacterial activity within the Clinical and Laboratory Standards Institute (CLSI) levels mainly against P. aeruginosa ATCC 27853 (MIC 8-128 µg/mL) and MRSA (MIC 32-128 µg/mL). In addition, the in vitro toxicity showed all derivatives with no hemolytic effects on healthy human erythrocytes. Furthermore, the derivatives showed satisfactory theoretical absorption, distribution, metabolism, excretion, toxicity (ADMET) parameters, and a similar profile to antibiotics currently in use. Finally, the in silico evaluation pointed to a structure-activity relationship related to lipophilicity for these compounds. This feature may help them in acting against Gram-negative strains, which present a rich lipid cell wall selective for several antibiotics. Conclusion: Our data showed the potential of this series for exploring new and more effective antibacterial activities in vivo against other resistant bacteria.

DMAP-catalyzed Efficient and Convenient Approach for the Synthesis of 3,3′-(Arylmethylene)bis(2-Hydroxynaphthalene-1,4-Dione) Derivatives

“…The formation of 3,3'-(arylmethylene)bis(2-hydroxynaphthalene-1,4-diones) 3a-i could be explained by proposed mechanism described in Scheme 2. It is supposed that initially DMAP catalyzed the Knoevenagel condensation between lawsone (1) and aldehyde 2 to give intermediate 5, which underwent dehydration to furnish 3-(1-arylmethylidene)-1,2,3,4-tetrahydro-12,4-naphthalenetrione (6). The naphthalenetrione (6) reacted in a Michael manner with the second molecule of lawsone (1) under DMAP-catalysis to generate the intermediate 7, followed by elimination of DMAP catalyst and tautomerization to afford product 3a-i.…”

“…4 Particularly, trifluoromethyl-substituted compound induced apoptosis in the glioma cells by inducing the caspase dependent apoptotic pathways via ROS and downregulating the PI3 K/AKT/mTOR pathway. Several bis -lawsone derivatives were found to exhibit antioxidant, antifungal, 5 antibacterial, 6 and antileishmanial activities 7 as well as inhibit against HIV-1 integrase, 8 and H5N1 neuraminidase. 9…”

“…4 Particularly, trifluoromethyl-substituted compound induced apoptosis in the glioma cells by inducing the caspase dependent apoptotic pathways via ROS and downregulating the PI3 K/AKT/mTOR pathway. Several bis-lawsone derivatives were found to exhibit antioxidant, antifungal, 5 antibacterial, 6 and antileishmanial activities 7 as well as inhibit against HIV-1 integrase, 8 and H5N1 neuraminidase. 9 Due to the broad biological relevance of 3,3´-(arylmethylene)bis(2-hydroxynaphthalene-1,4-diones), considerable efforts have been paid on the improvement of synthetic approaches of this class of compounds for the past decades.…”

“…Due to the broad biological relevance of 3,3´-(arylmethylene) bis (2-hydroxynaphthalene-1,4-diones), considerable efforts have been paid on the improvement of synthetic approaches of this class of compounds for the past decades. Literature methods are mostly based on acid-catalyzed condensation between lawsone and aldehydes using LiCl, 10,11 sulfuric acid, 12 sulfamic acid, 13 camphor sulfonic acid, 14 β -alanine/AcOH, 7 L -aminoacids, 6 and ionic liquilds 15 as catalyst. Several bio-derived catalysts such as lipase, 16 chitosan, and O -carboxymethyl chitosan 17 were employed in these reactions.…”

Synthetic Derivatives against Wild-Type and Non-Wild-Type Sporothrix brasiliensis: In Vitro and In Silico Analyses

“…Seventy-eight novel chemical derivatives of seven different classes (pyrazoles, pyrazolones, quinolones, naphthoquinones, hydrazones, n-phthalimides and quinones) were screened by disk diffusion antimicrobial sensitivity test (adapted Kirby-Bauer methodology) [55].…”